Role of pulmonary intravascular macrophages in endotoxin-induced lung inflammation and mortality in a rat model.
BACKGROUND
Bile-duct ligated (BDL) rats recruit pulmonary intravascular macrophages (PIMs) and are highly susceptible to endotoxin-induced mortality. The mechanisms of this enhanced susceptibility and mortality in BDL rats, which are used as a model of hepato-pulmonary syndrome, remain unknown. We tested a hypothesis that recruited PIMs promote endotoxin-induced mortality in a rat model.


METHODS
Rats were subjected to BDL to induce PIM recruitment followed by treatment with gadolinium chloride (GC) to deplete PIMs. Normal and BDL rats were treated intravenously with E. coli lipopolysaccharide (LPS) with or without GC pre-treatment followed by collection and analyses of lungs for histopathology, electron microscopy and cytokine quantification.


RESULTS
BDL rats recruited PIMs without any change in the expression of IL-1beta, TNF-alpha and IL-10. GC caused reduction in PIMs at 48 hours post-treatment (P < 0.05). BDL rats treated intravenously with E. coli LPS died within 3 hours of the challenge while the normal LPS-treated rats were euthanized at 6 hours after the LPS treatment. GC treatment of rats 6 hours or 48 hours before LPS challenge resulted in 80% (1/5) and 100% (0/5) survival, respectively, at 6 hours post-LPS treatment. Lungs from BDL+LPS rats showed large areas of perivascular hemorrhages compared to those pre-treated with GC. Concentrations of IL-1beta, TNF-alpha and IL-10 were increased in lungs of BDL+LPS rats compared to BDL rats treated with GC 48 hours but not 6 hours before LPS (P < 0.05).


CONCLUSIONS
We conclude that PIMs increase susceptibility for LPS-induced lung injury and mortality in this model, which is blocked by a reduction in their numbers or their inactivation.
Gill
Sukhjit S
SS
Department of Veterinary Biomedical Sciences, University of Saskatchewan, Saskatoon, SK S7N5B4, Canada. sukhjeet_gill@hotmail.com
Suri
Sarabjeet S
SS
Janardhan
Kyathanahalli S
KS
Caldwell
Sarah
S
Duke
Tanya
T
Singh
Baljit
B
D000818:Animals; D004195:Disease Models, Animal; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects / Q000276:immunology* / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D008297:Male; D011014:Pneumonia / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D011652:Pulmonary Circulation / Q000276:immunology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013534:Survival; D015996:Survival Rate
D008070:Lipopolysaccharides